The goal of this research is the development of more accurate methods for molecular simulations of solvated proteins, and their application to forefront problems in structural biology and biophysical chemistry. There are three specific aims: (1) further develop implicit solvent all atom effective potentials for biomolecular simulations and methods for their optimization, (2) use these implicit solvent models to: explore the molecular basis for protein-ligand binding specificity, study the native to molten globule protein "melting" transition, continue work on protein structure determination using sparse experimental data, and (3) characterize protein dynamics more accurately and over longer times, by combining information from simulations with those from NMR and single molecule optical experiments analyzed in new ways. These projects will build on the progress made during the current grant period in the development of "state of the art" effective potentials for protein simulations and forefront applications which are best suited to investigation using all atom models.